San Diego, CA—The investigational chimeric antigen receptor (CAR) T-cell therapy KTE-C19 achieved complete responses that were durable for >1 year in more than 75% of patients with aggressive lymphomas who had no other effective treatment options, according to results from the phase 2 pivotal clinical trial ZUMA-1 that were presented by Sattva S. Neelapu, MD, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, at the 2016 American Society of Hematology meeting.
The majority of the patients in the study had diffuse large B-cell lymphoma (DLBCL) and a smaller proportion of patients had transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).
An interim analysis of the ZUMA-1 clinical trial showed that more than 75% of patients with DLBCL responded to KTE-C19, and nearly 50% of patients had a complete response. Remissions were ongoing after 12 months, with some patients remaining in remission after several years.
“The complete response rate is 6-fold higher compared with historical outcomes in this patient population. This is the first pivotal multicenter study of anti-CD19 CAR T-cells in refractory aggressive non-Hodgkin lymphoma,” said Dr Neelapu. The FDA approval of KTE-C19 is expected to be filed in 2017.
CAR T-cell therapy uses a patient’s extracted T-cells, which are genetically engineered, in this case, with CD19 receptors. The T-cell population is expanded in vitro and reinfused into the patient. Manufacturers are attempting to develop CAR T-cells that are engineered to hit other antigens, including CD20 and CD44.
CAR T-cell therapy is associated with numerous adverse events, including cytokine release syndrome and neurologic events. Physicians need to be educated to deliver this therapy.
“Adverse effect management was implemented across all 22 sites where patients were treated. It is critical to educate physicians at different centers on how to manage the side effects. The ZUMA-1 investigators had extensive education in the management of adverse events before the study was conducted. It is critical for investigators and staff who take care of these patients to be educated about cytokine release syndrome and neurologic events before proceeding with CAR T-cell treatment,” said Dr Neelapu. There were investigators in this clinical trial who had no experience in using CAR T-cell therapy before the study started, he added.
Study Design
The ZUMA-1 clinical trial included 111 patients with DLBCL, TFL, or PMBCL. CAR T-cell therapy manufacturing was successful in 99% of patients (91% received treatment), and the turnaround time was approximately 17 days from apheresis to the arrival of CAR T-cell therapy at the clinical site.
At the data cutoff (in August 2016) for the interim analysis, 73 patients with DLBCL and 20 patients with TFL or PMBCL were evaluable for objective response rate (ORR) at 1 month; the ORR was 68% and 80%, respectively; and complete response was 33% and 55%, respectively.
Of these patients, 62 were evaluable for the primary end point. In the 51 patients with DLBCL, the best ORR was 76%, and the complete response was 47%, with at least 3 months of follow-up. In the 11 patients with TFL or PMBCL, the best ORR was 91%, and the complete response was 73%, with at least 3 months of follow-up. In a subgroup analysis, the complete response rate was 75% in the 12 patients whose disease relapsed after autologous stem-cell transplantation and 47% in patients whose disease was refractory to second-line or higher therapy.
The safety evaluation was based on 93 patients. Grade 3 or higher adverse events were reported in 93% of patients with DLBCL and in 90% of patients with TFL or PMBCL. Grade 3 cytokine release syndrome occurred in 14% of patients with DLBCL and in 10% of patients with TFL or PMBCL. Grade 3 neurologic events occurred in 25% of patients with DLBCL and in 45% of patients with TFL or PMBCL. Cytokine release syndrome and neurologic events were generally reversible.
The responses are similar to other studies of CAR T-cell therapy and are not surprising, said Selina M. Luger, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, who was not involved in the study. The most important part of this study is the broader applicability of this therapy, she added.
“What is remarkable is not the actual effect, but the fact that they were able to do this in a multicentered fashion among many centers with no previous experience,” Dr Luger concluded.